The applicants have proposed NMDA receptor hypofunction (NRHypo) as a disease mechanism that can help explain neurodegeneration in Alzheimer's disease (AD), based on evidence that the NMDA receptor system is markedly hypofunctional in the brains of patients with AD, and of evidence that when a sustained NRHypo state is induced in the adult rat brain (by drugs that block NMDA glutamate receptors), this triggers a widespread pattern of neuronal degeneration resembling that seen in AD. While this pattern is similar, the exact correspondence remains unclear in part because several brain areas in primate have no homologue in rat. Thus this project seeks to characterize NRHypo degeneration in non- human primates in order to better determine the importance of this neurodegenerative process for AD. In addition because two NMDA antagonists (ketamine and nitrous oxide [laughing gas, N2O]) are currently in clinical use it is critical to determine the risk of inducing this neurodegeneration in patients who are exposed to these agents in the clinical setting. The applicants have generated preliminary evidence documenting that monkeys are susceptible to this neurodegenerative process. In Aim #1 three NMDA antagonists (MK-801, ketamine and N20) will be studied in adult monkeys in order to confirm susceptibility of adult monkeys to NRHypo neurodegeneration and clarify the dose threshold for triggering neurodegeneration. Previous we have shown that prepubertal rats are insensitive to the NRHypo neurodegenerative mechanism. Preliminary evidence indicates that the susceptibility of monkeys to NRHypo neurodegeneration has a similar age dependency profile Thus work in Aim #2 seeks to confirm these early results. In rats we have identified several different classes of receptor5-specific drugs that prevent NRHYPO neurodegeneration. In Aim #3 we will study the potential of these agents to provide similar protection against NRHYPO neurodegeneration in the adult non-human profile.